SpringWorks Therapeutics has announced the completion of its New Drug Application (NDA) submission to the U.S. Food and Drug Administration (FDA) for mirdametinib, an investigational MEK inhibitor, aimed at treating pediatric and adult patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN). This submission marks a significant step toward potentially providing a new treatment option for this challenging condition.
The NDA is supported by data from the pivotal Phase 2b ReNeu trial (NCT03962543), which evaluated mirdametinib in patients aged 2 years and older with NF1-associated PN causing significant morbidity. The results, presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, demonstrated that mirdametinib treatment led to significant objective response rates, as confirmed by blinded independent central review. These responses were both deep and durable, with improvements observed in pain and health-related quality of life, alongside a manageable safety profile across both adult and pediatric cohorts.
ReNeu Trial Details
The ReNeu trial is an ongoing, multi-center, open-label Phase 2b study assessing the efficacy, safety, and tolerability of mirdametinib in patients aged 2 years and older with inoperable NF1-associated PN causing significant morbidity. The trial enrolled 114 patients who received mirdametinib at a dose of 2 mg/m2 twice daily (maximum dose of 4 mg twice daily) on a 3-week on, 1-week off dosing schedule. The primary endpoint was a confirmed objective response rate, defined as a ≥ 20% reduction in target tumor volume during the 24-cycle treatment phase, as measured by MRI and assessed by blinded independent central review. Secondary endpoints included safety and tolerability, duration of response, and changes from baseline in patient-reported outcomes to Cycle 13.
Neurofibromatosis Type 1 (NF1) and Plexiform Neurofibromas (PN)
Neurofibromatosis type 1 (NF1) is a rare genetic disorder resulting from mutations in the NF1 gene, which encodes neurofibromin, a key suppressor of the MAPK pathway. NF1 affects approximately 1 in 2,500 individuals globally, with around 100,000 patients in the United States. The condition presents with a variety of symptoms, including abnormal pigmentation, skeletal deformities, tumor growth, and neurological complications. Patients with NF1 face a reduced life expectancy of 8 to 15 years compared to the general population.
Approximately 30-50% of NF1 patients develop plexiform neurofibromas (PN), tumors that grow along the peripheral nerve sheath. These tumors can cause severe disfigurement, pain, and functional impairment, and in rare cases, can be fatal. NF1-PNs are typically diagnosed within the first two decades of life and can be aggressive, growing rapidly during childhood. Surgical removal is challenging due to the infiltrative growth pattern and can result in permanent nerve damage.
Mirdametinib: A MEK Inhibitor
Mirdametinib is a potent, oral, CNS-penetrant, allosteric small molecule MEK inhibitor. It is currently under investigation as a monotherapy for NF1-PN and low-grade glioma (LGG), and as a combination therapy for biomarker-defined metastatic solid tumors. Mirdametinib is designed to inhibit MEK1 and MEK2, which are crucial components of the MAPK pathway, a key signaling network regulating cell growth and survival.
The FDA and the European Commission have granted Orphan Drug designation for mirdametinib for the treatment of NF1. The FDA has also granted Fast Track designation for patients aged 2 years and older with NF1-PN that are progressing or causing significant morbidity, as well as Rare Pediatric Disease designation for the treatment of NF1.
Future Plans
SpringWorks Therapeutics plans to file a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA) for mirdametinib for the treatment of children and adults with NF1-PN in the second half of 2024. Saqib Islam, Chief Executive Officer of SpringWorks, stated, "We are pleased to be one step closer towards our goal of bringing mirdametinib to patients with NF1-PN in the U.S. and believe that our ReNeu data support the potential for mirdametinib to be a differentiated and best-in-class therapy for both children and adults living with this devastating disease."
